Two principal Immunopathogenetic features characterize the autoimmune inflammatory myopathies, polymyositis, dermatomyositis, and related diseases: lymphocytic destruction of muscle cells, and humoral autoimmunity distinguished by a striking set of disease-specific autoantibodies. Although the muscle cell destruction is mediated by lymphocytes, the autoantibodies, particularly those directed against the family of functionally related but structurally diverse aminoacyl-tRNA synthetases, seem to offer a useful window on the disease and have been the focus of much of this group's research for a number of years. This work continues, although at a diminished intensity. Currently, the major project related to the autoantibodies is an attempt to obtain stable crystals of the principal autoantigenic target, histidyl-tRNA synthetase. The apparently satisfactory recombinant protein made in baculovirus yielded crystals that gave unsatisfactory x-ray reflections, so a bacterial version is under construction. Recently our attention has focused on the lymphocytic destruction. The tissue damage, in contract to the majority of autoimmune tissue damage, is associated with a predominantly CD-8+ infiltrate. Furthermore, muscle is one of the few tissues in which MHC Class I is constitutively absent, but in myositis, it is markedly up-regulated on myocytes, raising the possibility that this up-regulation plays a role in initiating and sustaining the inflammation. The following areas are being pursued: 1) Study of the cytokines and chemokines in inflamed patient muscle biopsies. It appears that the pro-inflammatory cytokines are usually absent, but that the chemokine, MIP-1alpha is almost universally present. 2) Study of the regulation of MHC Class I in cultured muscle cells, including the influence of cytokines and chemnokines on its regulation. 3) Attempts to construct transgenic mice in which MHC Class I is constitutively up-regulated in myocytes to determine whether that is sufficient stimulus to incite tissue damage and inflammation as it has been in several other systems. 4) Attempts to identify any unique peptides which occupy MHC Class I in cultured muscle cells but not in other cells (B cells) from the same individual in the expectation that such peptides are the targets of the tissue-specific cytotoxic attack that characterizes myositis. 5) Studying the effect of methimazole, an anti-thyroid drug which down-regulated Class I in rodents, on Class I of muscle and lymphocytes in patients receiving the drug in a therapeutic trial (see Z01 AR 41076-08 ARB).